This invention is in the field of optical measuring techniques and relates to a method for determining desired parameters of the patient""s blood, for example, the concentration of a substance in blood, such as glucose, hemoglobin, drugs or cholesterol, or other important blood parameters such as oxygen saturation. The invention is particularly useful for non-invasive measurements.
Optical methods of determining the chemical composition of blood are typically based on spectrophotometric measurements enabling the indication of the presence of various blood constituents based on known spectral behaviors of these constituents. These spectrophotometric measurements may be effected either in vitro or in vivo. The measurements in vitro are invasive, i.e. require a blood sample to be physically withdrawn and examined. At present, these measurements have become unpopular, due to the increasing danger of infection.
The non-invasive optical measurements in vivo may be briefly divided into two main groups based on different methodological concepts. The first group represents a so-called xe2x80x9cDC measurement techniquexe2x80x9d, and the second group is called xe2x80x9cAC measurement techniquexe2x80x9d.
According to the DC measurement technique, any desired location of a blood perfused tissue is illuminated by the light of a predetermined spectral range, and the tissue reflection and/or transmission effect is studied. Although this technique provides a relatively high signal-to-noise ratio, as compared to the AC measurement technique, the results of such measurements depend on all the spectrally active components of the tissue (i.e. skin, blood, muscles, fat, etc.), and therefore need to be further processed to separate the xe2x80x9cblood signalsxe2x80x9d from the detected signals. Moreover, proportions of the known components vary from person to person and from time to time. To resolve this problem, calibration must periodically be provided, which constitutes an invasive blood test and therefore renders the DC technique of optical measurements to be actually invasive.
The AC measurement technique focuses on measuring only the xe2x80x9cblood signalxe2x80x9d of a blood perfused tissue illuminated by a predetermined range of wavelengths. To this end, what is actually measured is a time-dependent component only of the total light reflection or light transmission signal obtained from the tissue. A typical example of the AC measurement technique is the known method of pulse oximetry, wherein a pulsatile component of the optical signal obtained from a blood perfused tissue is utilized for determining arterial blood oxygen saturation. In other words, the difference in light absorption of the tissue measured during the systole and the diastole is considered to be caused by blood that is pumped into the tissue during the systole phase from arterial vessels, and therefore has the same oxygen saturation as in the central arterial vessels.
The major drawback of the AC measurement technique is its relatively low signal-to-noise ratio, especially in cases where an individual has a poor cardiac output, insufficient for providing a pulsatile signal suitable for accurate measurements.
Various methods have been suggested to enhance the natural pulsatile signal of an individual for effecting non-invasive optical measurements, and are disclosed for example in the following patents: U.S. Pat. No. 4,883,055; U.S. Pat. No. 4,927,264; and U.S. Pat. No. 5,638,816. All these techniques utilize the artificially induced volumetric changes of either arterial or venous blood. Since each of these techniques is specific about the kind of blood under test, they all impose severe restrictions on the value of the artificially applied pressure. This is due to different xe2x80x9cdisturbing pressure valuesxe2x80x9d allowed for different kinds of blood flow. It means that for each kind of blood flow, there is a pressure value that disturbs specifically this kind of flow much more than any other kind. For example, when the artificial pressure at a value of 60 mmHg is applied to a proximal body part, the venous blood flow will be affected, whereas the arterial blood flow will not be affected, since the individual""s diastolic pressure is usually higher than 60 mmHg. The applied artificial pressure definitely should not exceed pressures causing substantial deformation of the tissue, since only blood flow changes are supposed to be detected by optical measurements, and the measurements are to be effected in synchronism with the artificial pulse. However, if such an artificially induced pulse causes uncontrollable changes of the optical properties of the tissue, these changes cannot be distinguished from those caused by the blood flow fluctuations which are the target of the measurements.
There is a need in the art to facilitate the determination of various parameters of the patient""s blood, by providing a novel method of optical measurements which can be utilized in a non-invasive manner for in vivo determination of such parameters as the concentration of a substance in blood (e.g., hemoglobin, glucose), oxygen saturation, the difference between the refraction indexes of hemoglobin and plasma in the patient""s blood, and/or Erythrocyte Aggregation Rate (EAR).
It is a major feature of the present invention to provide such a method that is universal and does not depend on such conditions as concrete kinetics, aggregation shape, etc. which vary from patient to patient.
The present invention takes advantage of the technique disclosed in the co-pending application assigned to the assignee of the present application. The main idea underlying this technique is based on the fact that the light response characteristics (i.e., absorption and/or scattering) of a blood perfused medium dramatically changes when a character of blood flow changes. It has been found by the inventors, that the optical characteristics of a blood perfused fleshy medium (e.g., the patient""s finger) start to change in time, when causing blood flow cessation. In other words, once the blood flow cessation state is established, the optical characteristics start to change dramatically, such that they differ from those of the fleshy medium with a normal blood flow by about 25 to 45%, and sometimes even by 60%. Hence, the accuracy (i.e., signal-to-noise ratio) of the optical measurements can be substantially improved by performing at least two timely separated measurement sessions, each including at least two measurements with different wavelengths of incident radiation.
The main idea of the present invention is based on the investigation that the changes of the light response of a blood perfused fleshy medium at the state of the blood flow cessation (either monotonous or not, depending on the wavelength of incident radiation) are caused by the changes of the shape and average size of the scattering centers in the medium, i.e., red blood cells (RBC) aggregation (Rouleaux effect). The main principles of this effect are disclosed, for example, in the article xe2x80x9cQuantitative Evaluation of the Rate of Rouleaux Formation of Erythrocytes by Measuring Light Reflection (xe2x80x9cSyllectometryxe2x80x9d)xe2x80x9d, R. Brinkman et al., 1963.
At the state of the blood flow cessation, when there is actually no blood flow, no shear forces prevent the erythrocytes"" aggregation process. Hence, the light response (transmission) of the blood perfused fleshy medium undergoing the occlusion, which causes the blood flow cessation, can be considered as the time dependence of scattering in a system with growing scatterers.
Generally, light response of a medium is defined by the scattering and absorption properties of the medium. According to the model of the present invention, at the state of blood flow cessation under proper conditions, the crucial parameter defining the time evolution of the light response is a number of erythrocytes in aggregates. Therefore, it can be concluded that the average size of aggregates also changes with time. The scattering properties of blood depend on the size and shape of aggregates (scatterers). As for the absorption properties, they do not depend on the shape and size of scatterers, but depend only on the volume of the components.
Although the time increase of the size of aggregates for a specific patient is unknown, as well as a concrete geometry of aggregates or concrete RBC""s refraction index, there exists a parameter, which is universal and does not significantly depend on concrete kinetics, aggregation shape, etc. This parameter is determined as the parametric slope of the line Txcex2(Txcex1) (or log Txcex2(Log Txcex1)), wherein Txcex2 is the time dependence of the transmission of the medium irradiated with the wavelength xcex2, and Txcex1 is the time dependence of the transmission of the medium irradiated with the wavelength xcex1. This enables the explicit usage of the size of aggregates (i.e., the values that are unknown in experiments in vivo) to be eliminated. The time period considered in the determination of the parametric slope may be the so-called xe2x80x9cinitial time intervalxe2x80x9d of the entire time period during which the measurements were made at the blood flow cessation state, or the so-called xe2x80x9casymptotic time intervalxe2x80x9d that follows the initial time interval. The initial time interval is distinguished from the asymptotic time interval, in that the transmission signals more strongly change with time during this interval, as compared to that of the asymptotic time interval.
To determine the parametric slope aimed at determining a desired parameter of blood, the two wavelengths are selected in accordance with the parameter to be determined. For example, if the hemoglobin concentration is to be determined, the selected wavelengths are in those ranges, where the absorption properties of the hemoglobin and plasma are more sharply expressed, namely, the ranges of 600-1000 nm and 1100-1400 nm. If the oxygen saturation is to be determined, the selected wavelengths lie in the ranges where the difference in the absorption of hemoglobin (Hb) and oxyhemoglobin (HbO2) are more sharply expressed, namely, the ranges of 600-780 nm (HbO2 sensitive range) and 820-980 nm (Hb sensitive range). When dealing with the glucose concentration, the spectral ranges of 1500-1600 nm may be added to the above-mentioned range of 600-1300 nm for selecting the two wavelengths, respectively.
Having determined the parametric slope for a specific patient, a corresponding calibration curve presenting the corresponding parametric slope as the function of the desired parameter is used for determining the desired parameter for the specific patient. The calibration curve, or a set of such curves for different parameters, is previously prepared and stored as reference data. The calibration curve is prepared by applying measurements of the present invention and the conventional ones to different patients, and determining the parametric slope and the desired parameter, respectively. For the determination of oxygen saturation, generally, a calibration curve may be prepared by applying measurements of the present invention to a specific patient, but at the multiple-occlusion mode at the blood flow cessation state in a breath hold experiment.
Additionally, it was found that for one wavelength of the incident radiation the time dependence of transmission signal, i.e., T(t), asymptotically falls, and for the another wavelength it grows. This fact allows for constructing a certain rouleaux geometry factor (RGF). This RGF essentially involves the different time evolutions of light responses at the different wavelengths of incident radiation, and may serve as one of the key-parameters for attributing the measurement results to the certain calibration curve.
The RGF may be constructed in different ways. For example, the RGF can be taken as a certain xe2x80x9ccut-offxe2x80x9d wavelength xcex0 corresponding to the transmission value staying nearly constant with time. This cut-off wavelength can be determined as the wavelength corresponding to the condition xcex94T/xcex94t=0 (or xcex94(log T)/xcex94t=0). On the other hand, it is known from literature and is theoretically obtainable, that a function K(x(nHbxe2x88x92npl)), which describes the effects of light diffraction on particles depending on the model used, has several extremum values. Here, x=2xcfx80a/xcex, a being the erythrocyte size; nHb is the refraction index of hemoglobin and npl is the refraction index of liquid surroundings, i.e., plasma, which is similar to water by its optical characteristics. It is also known, and is shown in the description below, that the transmission signal is almost proportional to this function K. It is thus evident that the existence of extremum values of the function K is the physical reason for the cut-off wavelengths appearing. Having determined this cut-off wavelength xcex0, the scattering function K(x(nHbxe2x88x92npl)) in the particular case (or another relevant diffraction related function) can be used for determining a corresponding value of the parameter as x(nHbxe2x88x92npl) and the difference (nHbxe2x88x92npl) for a specific patient.
Indeed, since the erythrocyte size, a, and the difference (nHbxe2x88x92npl) lie in certain accepted ranges, the ranges for the product x(nHbxe2x88x92npl) can be defined. The extremum value of the function K corresponds to a certain value of this product, and to the cut-off wavelength xcex0 which can be determined as described above. Considering that erythrocyte is a biconcave disk or spheroid having its small and long sizes, and that during the aggregation process the erythrocytes adhere to each other along their long surfaces (or in different geometries), at the asymptotic time interval, the actual aggregate size contributing to the scattering after the averaging is equal to the effective transverse size of the aggregate, which in the particular case may be taken, for example, of the order of small size a of the single erythrocyte.
Another example of the RGF may be such a wavelength, xcexmax, that corresponds to such a condition that the ratio xcex94(log T)/xcex94t as the function of wavelength xcex has its maximal value. This enables to provide an additional calibration parameter, which is specific for a certain blood condition of a specific patient. Other peculiarities, well defined mathematically, of the ratio xcex94(log T)/xcex94t as the function of wavelength and/or time t enable to characterize the blood conditions of a specific patient, which can be utilized for calibration purposes.
Hence, the knowledge of the RGB for a specific patient enables the determination of the difference (nHbxe2x88x92npl) for this patient. The knowledge of this data is very important for diagnostic purposes. For example, it is known that the concentration of glucose affects the difference (nHbxe2x88x92nH2O). Furthermore, numerous sets of calibration curves can be prepared, wherein each such set corresponds to a certain value of the RGB, and each calibration curve in the set corresponds to a certain blood parameter. This enables to obtain more precise information about the patient""s blood.
Generally speaking, the present invention presents a technique for obtaining and analyzing the time changes of the spectral dependence of the light response (transmission) of the patient""s blood at the state of blood flow cessation, wherein these changes result from the effect of scattering on particles of different size (erythrocyte aggregates). The state of blood flow cessation is preferably obtained in vivo by applying over-systolic pressure to the patient""s blood perfused fleshy medium, e.g., his finger, but can also be obtained in vitro, by providing the flow of the patient""s blood sample into a cuvette and occluding the flow for a certain time period.
For the calculation of the optical properties of blood (reflection and transmission coefficients), properties of the entire system should be connected with the scattering and absorption properties of the unit of the system volume. To this end, the scattering and absorption coefficients are evaluated. As indicated above, for blood, the absorption coefficient xcexcabs does not depend on the shape of particles and is their sizes. What does depend on the particle size is the scattering coefficient xcexcscat. This conclusion is true for various models of multiple scattering theories, such as the model of Twersky, diffusion models, model of Hemenger, model of Rogozkin, and Small-Angle model.
There is thus provided according to one aspect of the present invention, a method of optical measurements of at least one desired parameter of a patient""s blood, the method comprising the steps of:
providing a state of blood flow cessation of the patient""s blood within a measurement region, and maintaining the blood-flow cessation state during a predetermined time period;
performing measurement sessions within said predetermined time period, each measurement session including at least two measurements with different wavelengths of incident light, and obtaining measured data representative of the time dependence of light response of the blood in the measurement region;
analyzing the measured data for determining said at least one desired parameter, extracted from optical characteristics associated with erythrocytes aggregation process during the state of the blood flow cessation.
The term xe2x80x9cmeasurement sessionsxe2x80x9d used herein signifies either timely separated measurements, or continuous measurements over a certain time interval lying within the predetermined time period during which the blood flow cessation state is maintained.
The state of blood flow cessation can be provided by occluding the blood flow within a measurement region of the patient""s blood perfused fleshy medium, by applying over systolic pressure to the medium. In this case, the pressure is applied at a first location on the patient""s organ, while measurements are applied to a second location downstream of the first location with respect to the direction of normal blood flow. In this case, the measurements start upon detecting the existence of the blood flow cessation state, through preliminary optical measurements. Occlusion is maintained during a predetermined period of time insufficient for irreversible changes in the fleshy medium, ranging generally from one second to several minutes. However, the same measurements can be applied to the patient""s blood sample in a cuvette.
The analysis of the measured data may include the determination of a parametric slope for the specific patient, in which case certain reference data is utilized in the form of a calibration curve presenting the parametric slope as a function of values of the desired parameter. For the purposes of this specific application, the different wavelengths are preferably selected in accordance with the blood parameter to be determined. If the concentration of a substance in the patient""s blood is to be determined, the use of two different wavelengths is sufficient.
Alternatively or additionally, the analysis of the measured data includes the determination of an RGF. The term xe2x80x9cRGFxe2x80x9d used herein is a factor characterizing the light response of blood in the state of blood flow cessation as the function of time and wavelengths of incident radiation, associated with the Rouleaux effect, or erythrocytes"" aggregation. In this case, the theoretical data indicative of a scattering function K(x(nHbxe2x88x92npl) may be used for determining the parameter x(nHbxe2x88x92npl) for the specific patient, if the xe2x80x9ccut-offxe2x80x9d wavelength serves as the RGF. To this end, preferably more than two different wavelengths of incident radiation are used in each measurement session and corresponding time variations of the transmission signals T(t) are measured in order to construct the proper RGF. Then, in the example of the cut-off wavelength, a ratio xcex94(log T)/xcex94t (or xcex94T/xcex94t) as the function of the wavelength xcex is determined for the time interval xcex94t that lies substantially within the asymptotic time interval. The point xcex0 corresponding to the condition xcex94(log T)/xcex94t=0 is the cut-off wavelength of incident radiation corresponding to a certain time stable transmission for a specific patient, which, in turn, corresponds to the extremum of the function K(x(nHbxe2x88x92npl)), within the accepted range of (x(nHbxe2x88x92npl)).
Another important parameter that can be obtained through the analysis of the measured data is the EAR, which is determined as the ratio xcex94T/xcex94t or xcex94(log T)/xcex94t. Generally, the use of only one wavelength of incident radiation is sufficient for this specific application. But practically, in order to enable the determination of several different parameters through the single measurement procedure, more than one wavelength is used.
According to another broad aspect of the present invention, there is provided a method of optical measurements of desired parameters of a patient""s blood extracted from optical characteristics associated with erythrocytes aggregation process during the state of the blood flow cessation, the method comprising the steps of:
providing the state of the blood flow cessation within a measurement region, and maintaining the blood-flow cessation state during a predetermined time period;
performing measurement sessions within said predetermined time period, each measurement session including at least two measurements with different wavelengths of incident light, and obtaining measured data representative of the time dependence of light response of the blood in the measurement region;
analyzing the measured data for determining said at least one desired parameter, by determining at least one parametric slope value and a Rouleaux Geometry Factor (RGF) for said patient, the RGF characterizing the changes of the light response of blood at the state of the blood flow cessation as the function of time and wavelengths of the incident radiation, associated with the erythrocytes"" aggregation.
According to yet another broad aspect of the present invention, there is provided a method of optical measurements of at least one desired parameter of blood of a specific patient extracted from optical characteristics associated with erythrocytes aggregation process during the state of blood flow cessation, the method comprising the steps of:
providing reference data in the form of a function describing diffraction effects on particles, K(x(nHbxe2x88x92nH2O), wherein x=2xcfx80a/xcex; a is the size of erythrocyte, nHb is the refraction index of hemoglobin and npl is the refraction index of water, xcex is the wavelength of incident radiation;
providing the state of the blood flow cessation and maintaining said state during a predetermined period of time;
performing measurement sessions within said predetermined time period, each measurement session including several measurements with different wavelengths of incident radiation, and obtaining measured data representative of the time dependence of light response signals;
analyzing the measured data for determining a Rouleaux Geometry Factor (RGF) for the specific patient, the RGF characterizing the changes of the light response of blood at the state of the blood flow cessation as the function of time and wavelengths of the incident radiation, associated with the erythrocytes"" aggregation.
According to yet another aspect of the present invention, there is provided a method of optical measurements of at least one desired parameter of blood of a specific patient extracted from optical characteristics associated with erythrocytes aggregation process during the state of blood flow cessation, the method comprising the steps of:
providing reference data in the form of at least one calibration curve corresponding to a parametric slope as a function of values of said desired parameter;
providing the state of the blood flow cessation within a measurement region, and maintaining the blood-flow cessation state during a predetermined time period;
performing timely separated measurement sessions within said predetermined time period, each measurement session including at least two measurements with different wavelengths of incident light, and obtaining the time dependence of transmission signals, wherein the at least two wavelengths are selected in accordance with the desired parameter to be determined;
analyzing the obtained data for determining the parametric slope value for said specific patient;
using said calibration curve for determining the value of said desired parameter for said specific patient.
There is also provided a measurement apparatus for performing non-invasive optical measurements of desired parameters of the patient""s blood.